Layered medical appliances and methods

ABSTRACT

Medical appliances may be formed of multilayered constructs. The layers of the constructs may be configured with various physical properties or characteristics. The disposition and arrangement of each layer may be configured to create an overall construct with a combination of the individual properties of the layers. Constructs may be used to create vascular prostheses or other medical devices.

RELATED APPLICATIONS

The present application is a continuation of U.S. application Ser. No.15/053,232, filed on Feb. 25, 2016, titled, “Layered Medical Appliancesand Methods,” which claims the benefit of U.S. Provisional ApplicationNo. 62/121,187, filed on Feb. 26, 2015, titled, “Layered MedicalAppliances and Methods,” the disclosure of each of which is incorporatedherein by reference in its entirety.

TECHNICAL FIELD

The present disclosure relates generally to medical appliances,including medical appliances composed of two or more layers of material.Medical appliances within the scope of this disclosure may includeporous layers, nonporous layers, fluid or cellular impermeable layers,and so forth. These layers may be included and/or arranged within theconstruct to affect the structural properties and/or biocompatibility ofthe medical appliance.

BRIEF DESCRIPTION OF THE DRAWINGS

The embodiments disclosed herein will become more fully apparent fromthe following description and appended claims, taken in conjunction withthe accompanying drawings. These drawings depict only typicalembodiments, which will be described with additional specificity anddetail through use of the accompanying figures in which:

FIG. 1 is a Scanning Electron Micrograph (SEM) (950×) of a seriallydeposited polytetrafluoroethylene (PTFE) fiber mat.

FIG. 2 is a Scanning Electron Micrograph (SEM) (950×) of an expandedpolytetrafluoroethylene (ePTFE) mat.

FIG. 3A is a perspective cut-away view of a medical appliance.

FIG. 3B is a cross-sectional view of the medical appliance of FIG. 3Ataken through line 3B-3B.

FIG. 3C is a cross-sectional view showing the layers of the medicalappliance of FIG. 3A.

FIG. 4 is a cross-sectional schematic view of the medical appliance ofFIG. 3A deployed within a body lumen.

FIG. 5 is a perspective view of a scaffolding structure for astent-graft.

DETAILED DESCRIPTION

Medical appliances may be deployed in various body lumens for a varietyof purposes. Stents and/or stent-grafts may be deployed, for example, inthe vascular system for a variety of therapeutic purposes, including thetreatment of occlusions within the lumens of that system. The currentdisclosure may be applicable to stents, stent-grafts, or other medicalappliances designed for the central venous (“CV”) system, peripheralvascular (“PV”) stents, abdominal aortic aneurysm (“AAA”) stents,bronchial stents, esophageal stents, biliary stents, coronary stents,gastrointestinal stents, neuro stents, thoracic aortic endographs, orany other stent or stent-graft. Further, the present disclosure may beequally applicable to other prostheses such as grafts, shunts, and soforth. Additionally, medical appliances comprising a continuous lumenwherein a portion of the longitudinal length is reinforced, for exampleby a metal scaffold, and a portion of the longitudinal length has noscaffold are also within the scope of this disclosure. Any medicalappliance composed of materials herein described may be configured foruse or implantation within various areas of the body, includingvascular, cranial, thoracic, pulmonary, esophageal, abdominal, or ocularapplication. Examples of medical appliances within the scope of thisdisclosure include, but are not limited to, stents, vascular grafts,stent-grafts, cardiovascular patches, reconstructive tissue patches,hernia patches, general surgical patches, heart valves, sutures, dentalreconstructive tissues, medical device coverings and coatings,gastrointestinal devices, blood filters, artificial organs, ocularimplants, and pulmonary devices, including pulmonary stents. Forconvenience, many of the specific examples included below referencestent-grafts. Notwithstanding any of the particular medical appliancesreferenced in the examples or disclosure below, the disclosure andexamples may apply analogously to any prostheses or other medicalappliance.

As used herein, the terms stent and stent-graft refer to medicalappliances configured for use within bodily structures, such as withinbody lumens. A stent or stent-graft may comprise a scaffolding orsupport structure, such as a frame, and/or a covering.

It will be readily understood that the components of the embodiments asgenerally described and illustrated in the Figures herein could bearranged and designed in a wide variety of different configurations.Thus, the following more detailed description of various embodiments, asrepresented in the Figures, is not intended to limit the scope of thedisclosure, but is merely representative of various embodiments. Whilethe various aspects of the embodiments are presented in drawings, thedrawings are not necessarily drawn to scale unless specificallyindicated.

The phrases” “coupled to” and “in communication with” refer to any formof interaction between two or more entities, including mechanical,electrical, magnetic, electromagnetic, fluid, and thermal interaction.Two components may be coupled to each other even though they are not indirect contact with each other. For example, two components may becoupled to each other through an intermediate component.

The directional terms “proximal” and “distal” are used herein to referto opposite locations on a stent or another medical appliance. Theproximal end of an appliance is defined as the end closest to thepractitioner when the appliance is disposed within a deployment devicewhich is being used by the practitioner. The distal end is the endopposite the proximal end, along the longitudinal direction of theappliance, or the end furthest from the practitioner. It is understoodthat, as used in the art, these terms may have different meanings oncethe appliance is deployed (i.e., the “proximal” end may refer to the endclosest to the head or heart of the patient depending on application).For consistency, as used herein, the ends labeled “proximal” and“distal” remain the same regardless of whether the appliance isdeployed.

The longitudinal direction of a stent or stent-graft is the directionalong the axis of a generally tubular stent or stent-graft. Inembodiments where an appliance is composed of a metal wire structurecoupled to one or more layers of a film or sheet-like component, such asa polymer layer, the metal structure is referred to as the “scaffolding”or “frame,” and the polymer layer as the “covering” or “coating.” Theterms “covering” and “coating” may refer to a single layer of polymer,multiple layers of the same polymer, or layers comprising distinctpolymers used in combination. Furthermore, as used herein, the terms“covering” and “coating” refer only to a layer or layers which arecoupled to a portion of the scaffold; neither term requires that theentire scaffold be “covered” or “coated.” In other words, medicalappliances wherein a portion of the scaffold may be covered and aportion may remain bare are within the scope of this disclosure.Finally, any disclosure recited in connection with coverings or coatingsmay analogously be applied to medical devices comprising one or more“covering” layers with no associated frame or other structure. Forexample, a hernia patch comprising any of the materials described hereinas “coatings” or “coverings” is within the scope of this disclosureregardless of whether the patch further comprises a frame or otherstructure. Similarly, a tubular graft or shunt may be comprised of thecovering or layered materials recited herein, with no associatedscaffolding structure.

Medical device coverings may comprise multilayered constructs, comprisedof two or more layers which may be serially applied. Further,multilayered constructs may comprise nonhomogeneous layers, meaningadjacent layers have differing properties. Thus, as used herein, eachlayer of a multilayered construct may comprise a distinct layer, eitherdue to the distinct application of the layers or due to differingproperties between layers. As layers may be identified by theirposition, structure, or function, an individual layer may notnecessarily comprise only a single material or a single microstructure.

Additionally, as used herein, “tissue ingrowth” and “cellularpenetration” refer to any presence or penetration of a biological orbodily material into a component of a medical appliance. For example,the presence of body tissues (e.g., collagen, cells, and so on) withinan opening or pore of a layer or component of a medical appliancecomprises tissue ingrowth into that component. Further, as used herein,“attachment” of tissue to a component of a medical appliance refers toany bonding or adherence of a tissue to the appliance, includingindirect bonds. For example, tissue of some kind (e.g., collagen) maybecome attached to a stent covering (including attachment via tissueingrowth), and another layer of biologic material (such as endothelialcells) may, in turn, adhere to the first tissue. In such instances, thesecond biologic material (endothelial cells in the example) and thetissue (collagen in the example) are “attached” to the stent covering.

Porous materials may be selectively permeable to various particles orbiologic elements based on the pore sizes of the material. For example,materials with pore sizes smaller than 20 micron may be impermeable tocells types larger than 20 micron, such as foreign body giant cells.Similarly, materials with pore sizes smaller than eight micron may beimpermeable to penetration by other cell types, such as red blood cells.In some embodiments, materials with pore sizes smaller than eight micronor smaller than six micron (including, for example, any value betweenzero and eight micron) may be impermeable to red blood cells.

As used herein, cellular impermeability does not require the completeexclusion of any cellular migration across a barrier. A material may beimpermeable to red blood cell migration, for example, even if a smallnumber of red bloods cells are able to cross the material. Accordingly,materials may be configured to substantially inhibit cellular migrationacross the material while meeting the definition of cellularimpermeability.

As used herein, red blood cell impermeable materials are materials whichsubstantially inhibit the transmural migration of red blood cells.Moreover, as used herein, to substantially inhibit transmural migrationof red blood cells means that, under biologic pressure (such as whenimplanted in the body), less than 0.1% of red blood cells which contactthe material wall will migrate across the material wall. Accordingly,this definition includes materials that inhibit the transmural migrationof the majority of red blood cells, without requiring completerestriction of all such cells. In some instances, materials with poresizes smaller than eight micron, including pore sizes smaller than sixmicron, or pore sizes of any value between zero and eight micron may beimpermeable to transmural migration of red blood cells. Other materials,for example, composite materials having individual layers of differingpore sizes, may likewise be impermeable to transmural migration of redblood cells.

In some instances, layers with porosities greater than six or eightmicron, when combined with additional layers to create a more tortuoustransmural path, may be impermeable to transmural migration of red bloodcells across the combined layers, even if no single layer has a porosityless than eight micron.

Still further, composite constructs comprising various layers of variousporosities may be impermeable to transmural migration of red bloodcells. In some embodiments, a construct comprised of layers of varyingporosities, coupled to a substantially nonporous layer may beimpermeable to transmural migration of red blood cells.

Moreover, constructs within the scope of this disclosure may be cellimpermeable to any cell type, meaning that less than 0.1% of cells whichcontact the construct (regardless of the cell type), will migrate acrossthe construct wall. Similarly, constructs within the scope of thisdisclosure may be tissue impermeable, meaning that less than 0.1% of themass or volume of tissue which contacts the construct will migrateacross the construct wall.

In one example, a cell impermeable tubular multilayered construct wasimplanted in an animal host for 30 days. Upon removal of themultilayered construct, no measurable amount of tissue was present onthe lumenal surface of the construct. Accordingly, materials implantedin an animal host for 30 days with no measurable transmural cell ortissue migration are cellular and tissue impermeable, as those terms areused herein. It was also observed that standard ePTFE stent-graftexhibited tissue growth on the lumenal surface when similarly implanted.

Additionally, materials or constructs may be impermeable to fluidicpassage across the material wall. Materials or layers with pore sizessmaller than 0.5 micron are herein referenced as being impermeable tofluidic passage, or fluid impermeable across the material or layer.

The pore sizes associated with any of the embodiments above may refer toaverage pore size as further defined below. It may also refer to poresizes determined by direct measurement techniques. The terms “generally”and “substantially” as used herein indicate that a parameter is within5% of a reference parameter. Thus, two quantities termed as generallyequivalent are within 5% of each other. Further, a generally orsubstantially impermeable membrane only varies from the defined poresizes above by 5%.

Lumens within the circulatory system are generally lined with a singlelayer (monolayer) of endothelial cells. This lining of endothelial cellsmakes up the endothelium. The endothelium acts as an interface betweenblood flowing through the lumens of the circulatory system and the innerwalls of the lumens. The endothelium, among other functions, reduces orprevents turbulent blood flow within the lumen. The endothelium plays arole in many aspects of vascular biology, including atherosclerosis,creating a selective barrier around the lumen, blood clotting,inflammation, angiogenesis, vasoconstriction, and vasodilation.

A therapeutic medical appliance which includes a covering of porous orsemi-porous material may permit the formation of an endothelial layeronto the porous surface of the blood contact side of the medical device.Formation of an endothelial layer on a surface, or endothelialization,may increase the biocompatibility of an implanted device. For example, astent which permits the formation of the endothelium on the insidediameter (blood contacting surface) of the stent may further promotehealing at the therapeutic region and/or have longer-term viability. Forexample, a stent coated with endothelial cells may be more consistentwith the surrounding body lumens, thereby resulting in less turbulentblood flow or a decreased risk of thrombosis, or the formation of bloodclots. A stent or stent-graft which permits the formation of anendothelial layer on the inside surface of the stent may therefore beparticularly biocompatible, resulting in less trauma at the point ofapplication, fewer side effects, and/or longer-term device viability.Medical appliances including a covering of porous or semi-porousmaterial may be configured to inhibit or reduce inflammatory responsesby the body toward the tissue-contacting side of the medical appliance,for example. Mechanisms such as an inflammatory response by the bodytoward the medical appliance may stimulate, aggravate, or encouragenegative outcomes, such as neointimal hyperplasia. For example, a deviceconfigured to permit tissue ingrowth and/or the growth or attachment ofendothelial cells onto the blood-contacting side of the device mayreduce the likelihood of negative flow characteristics and bloodclotting. Similarly, a device so configured may mitigate the body'sinflammatory response toward the material on, for example, thetissue-contacting side of the device. By modulating the evokedinflammatory response, negative outcomes such as the presence ofbioactive inflammatory macrophages and foreign body giant cells may bereduced. This may aid in minimizing the chemical chain of responses thatmay encourage fibrous capsule formation surrounding the device andevents stimulating neointimal hyperplasia.

Serially deposited fibers, such as rotational spun or electrospunmaterials, such as those described herein, may be used to compriseportions of medical appliances, such as stents, patches, grafts, and soforth. The present disclosure is applicable to any implantable medicalappliance, notwithstanding any specific examples included below. Inother words, though particular medical appliances, such as stents orpatches, may be referenced in the disclosure and examples below, thedisclosure is also analogously applicable to other medical appliances,such as those which comprise a covering or layer of polymeric material.

In some embodiments, serially deposited nanofibers (and/or microfibers)may be configured to permit interaction with nano-scale (and/ormicro-scale) body structures, such as endothelial cells, red bloodcells, collagen, and so forth.

Medical appliances may comprise two or more layers or materials. Theselayers, alone or in combination, may be designed or configured to impartvarious properties to the overall construct. For example, one or morelayers, and/or the combined characteristics of two or more layers, maycontrol the structural properties of the overall construct, such astensile strength, burst strength, flexibility, hoop strength, resistanceto radial compression, and so forth. Similarly, one or more layers,and/or the combined characteristics of two or more layers, may controlthe biocompatibility of the medical appliance. For example, porosity,fluid permeability, cellular permeability, and so forth may all affectthe biologic response to a medical appliance deployed within a patient'sbody.

Various structures, including medical appliances and related components,may comprise serially deposited fibers. Serially deposited fibers maycomprise polymeric fibers, ceramic fibers, and/or other materials. Insome embodiments, soft or fluidic materials are deposited in elongatestrands or fibers on a collector or substrate. After these fibers aredeposited, the shape or structure of the mat or lattice of fibers may beset by, for example, hardening of the material of the fibers. Forexample, polymeric materials may be deposited as fibers in the form of apolymeric dispersion and then heated to remove the solvent component ofthe dispersion and to set the structure of the polymeric fibers.Similarly, polymeric materials may be serially deposited as fibers whilethe material is in a heated or molten state. Cooling of the collectedfibers may tend to set the structure of the mat or lattice of fibers.The fibers comprising these mats or lattices may generally be on a microscale (fibers which are between one micron and one millimeter indiameter) and/or generally on a nano scale (fibers which are smallerthan one micron in diameter). FIG. 1 is an SEM (950×) of an exemplaryserially deposited fiber mat. The fibers of the mat of FIG. 1 weredeposited by rotational spinning of polytetrafluoroethylene (PTFE).

Serially deposited fiber mats or lattices refer to structures composedat least partially of fibers successively deposited on a collector, on asubstrate, on a base material, and/or on previously deposited fibers. Insome instances, the fibers may be randomly disposed, while in otherembodiments the alignment or orientation of the fibers may be somewhatcontrolled or follow a general trend or pattern. Regardless of anypattern or degree of fiber alignment, because the fibers are depositedon the collector, substrate, base material, and/or previously depositedfibers, the fibers are not woven, but rather serially deposited. Becausesuch fibers are configured to create a variety of structures, as usedherein, the terms “mat” and “lattice” are intended to be broadlyconstrued as referring to any such structure, including tubes, spheres,sheets, and so on. Furthermore, the term “membrane” as used hereinrefers to any structure comprising serially deposited fibers having athickness which is smaller than at least one other dimension of themembrane. Examples of membranes include, but are not limited to,serially deposited fiber mats or lattices forming sheets, strips, tubes,spheres, covers, layers, and so forth.

Rotational spinning is one example of how a material may be seriallydeposited as fibers. One embodiment of a rotational spinning processcomprises loading a polymer solution or dispersion into a cup orspinneret configured with orifices on the outside circumference of thespinneret. The spinneret is then rotated, causing (through a combinationof centrifugal and hydrostatic forces, for example) the flowablematerial within the spinneret to be expelled from the orifices. Thematerial may then form a “jet” or “stream” extending from the orifice,with drag forces tending to cause the stream of material to elongateinto a small diameter fiber. The fibers may then be deposited on acollection apparatus, a substrate, or other fibers. Once collected, thefibers may be dried, cooled, sintered, or otherwise processed to set thestructure or otherwise harden the fiber mat. For example, polymericfibers rotational spun from a dispersion may be sintered to removesolvents, fiberizing agents, or other materials as well as to set thestructure of the mat. In one embodiment, for instance, an aqueouspolytetrafluoroethylene (PTFE) dispersion may be mixed with polyethyleneoxide (PEO) (as a fiberizing agent) and water (as a solvent for thePEO), and the mixture rotational spun. Sintering by heating thecollected fibers may set the PTFE structure, evaporate off the water,and sublimate the PEO. Exemplary methods and systems for rotationalspinning can be found in U.S. patent application Ser. No. 13/742,025,filed on Jan. 15, 2013, and titled “Rotational Spun Material CoveredMedical Appliances and Methods of Manufacture,” which is hereinincorporated by reference in its entirety.

Rotational spinning processes and electrospinning processes may produceserially deposited fiber mats with differing characteristics. Forexample, as compared to electrospinning processes, rotational spinningmay exhibit superior yield, performance, and scaling. Rotationalspinning processes may exhibit greater repeatability, reliability, andquality compared to electrospinning. In other words, rotational spunfiber mats may exhibit more consistency within closer tolerances ascompared to electrospun fiber mats. Rotational spinning may be moredirectly scalable to large operations. Whereas electrospinning on alarge scale may entail high voltage and other difficulties that furtherintroduce time, cost, and variability, rotational spinning may moredirectly and simply scale, producing more consistent fiber mats.

Electrospinning is another embodiment of how a material may be seriallydeposited as fibers. One embodiment of an electrospinning processcomprises loading a polymer solution or dispersion into a syringecoupled to a syringe pump. The material is forced out of the syringe bythe pump in the presence of an electric field. The material forced fromthe syringe may elongate into fibers that are then deposited on agrounded collection apparatus, such as a collector or substrate. Thesystem may be configured such that the material forced from the syringeis electrostatically charged, and thus attracted to the groundedcollection apparatus. As with rotational spinning, once collected, thefibers may be dried, cooled, sintered, or otherwise processed to set thestructure or otherwise harden the fiber mat. For example, polymericfibers electrospun from a dispersion may be sintered to remove solvents,fiberizing agents, or other materials as well as to set the structure ofthe mat. As in rotational spinning, one embodiment of electrospinningcomprises electrospinning an aqueous PTFE dispersion mixed with PEO andwater (as a solvent for the PEO). Sintering by heating the collectedfibers may set the PTFE structure, evaporate off the water, andsublimate the PEO. Exemplary methods and systems for electrospinningmedical devices can be found in U.S. patent application Ser. Nos.13/826,618 and 13/827,790, both filed on Mar. 13, 2014, and both titled“Electrospun Material Covered Medical Appliances and Methods ofManufacture,” and U.S. patent application Ser. No. 13/360,444, filed onJan. 27, 2012, and titled “Electrospun PTFE Coated Stent and Method ofUse,” each of which is hereby incorporated by reference in itsentireties.

Rotational spinning and/or electrospinning may be utilized to create avariety of materials or structures comprising serially deposited fibers.The microstructure or nanostructure of such materials, as well as theporosity, permeability, material composition, rigidity, fiber alignment,and so forth, may be controlled or configured to promotebiocompatibility or influence interactions between the material andcells or other biologic material. A variety of materials may be seriallydeposited through processes such as rotational spinning andelectrospinning: for example, polymers, ceramics, metals, materialswhich may be melt-processed, or any other material having a soft orliquid form. A variety of materials may be serially deposited throughrotational spinning or electrospinning while the material is in asolution, dispersion, molten or semi-molten form, and so forth. Thepresent disclosure may be applicable to any material discussed hereinbeing serially deposited as fibers onto any substrate or in any geometrydiscussed herein. Thus, examples of particular materials or structuresgiven herein may be analogously applied to other materials and/orstructures.

Rotational spinning, electrospinning, or other analogous processes maybe used to create serially deposited fiber mats as disclosed herein.Throughout this disclosure, examples may be given of serially depositedfiber mats generally, or the examples may specify the process (such asrotational spinning or electrospinning) utilized to create the seriallydeposited fiber mat. It is within the scope of this disclosure toanalogously apply any process for creating serially deposited fibers toany disclosure or example below, regardless of whether the disclosurespecifically indicates a particular mat was formed according to aparticular process.

Expanded polytetrafluoroethylene (ePTFE) may also be used as a componentof a layered medical appliance in some embodiments. ePTFE may be formedwhen a sheet of PTFE is heated and stretched. The sheet of ePTFE may beformed, for example, by extrusion or other methods. Heating andstretching of the PTFE sheet to form ePTFE changes the microstructure ofthe sheet, making it more porous and creating nodes of material withfibrils of material extending there between. U.S. Pat. No. 3,664,915 ofW. L. Gore describes various processes for heating and stretching PTFEto create ePTFE. In some processes, the ePTFE will be expanded to agreater extent along a longitudinal direction as compared to atransverse direction. Thus some ePTFE mats may be described as having anaxis of expansion, or the direction in which the majority of theexpansion was done. In some instances the ratio of expansion in thelongitudinal direction to expansion in a transverse direction may bebetween 10:1 and 20:1. FIG. 2 is an exemplary SEM (950×) of an ePTFEmembrane.

In some applications, ePTFE may also be further processed after it hasbeen initially formed. Some such processes may densify the ePTFE,reducing the porosity and increasing the strength. In some instancessuch post-processing may be used to contract fibrils extending betweenthe nodes of the ePTFE to create a layer that is substantiallyimpermeable to tissue and/or fluid. Thus, ePTFE layers may be configuredwith various permeability characteristics, including layers which areimpermeable to cellular or tissue migration across the layer. Further,such post-processing may increase the strength of the layer due to theresulting work processing stresses created in the material.

Characteristics of mats, including serially deposited fibers and/orePTFE, may be determined in a variety of ways. For example, internodaldistance, or IND, of ePTFE can be used to characterize the degree ofexpansion and/or the porosity of the ePTFE. The internodal distancerefers to the average distance between adjacent nodes of the membrane.

Percent porosity is another measurement that may be used to characterizemembranes with porous sections. This method can be used, for example, tocharacterize ePTFE and/or serially deposited fibers. Percent porosityrefers to the percent of open space to closed space (or space filled byfibers) in a membrane or mat. Thus, the more open the structure is, thehigher the percent porosity measurement. In some instances, percentporosity may be determined by first obtaining an image, such as an SEM,of a material. The image may then be converted to a “binary image,” oran image showing only black and white portions, for example. The binaryimage may then be analyzed and the percent porosity determined bycomparing the relative numbers of each type of binary pixel. Forexample, an image may be converted to a black and white image whereinblack portions represent gaps or holes in the membrane while whiteportions represent the fibers or other structure of the membrane.Percent porosity may then be determined by dividing the number of blackpixels by the number of total pixels in the image. In some instances, acode or script may be configured to make these analyses andcalculations.

In some embodiments the “average pore size” of an ePTFE of seriallydeposited mat may be used as an alternate or additional measurement ofthe properties of the mat. The complex and random microstructure ofserially deposited mats, for example, presents a challenge to the directmeasurement of the average pore size of the mat. Average pore size canbe indirectly determined by measuring the permeability of the mat tofluids using known testing techniques and instruments. Once thepermeability is determined, that measurement may be used to determine an“effective” pore size of the serially deposited mat. As used herein, the“pore size” of a serially deposited mat and/or an expanded membranerefers to the pore size of a known membrane which corresponds to thepermeability of the serially deposited or expanded fabric when measuredusing ASTM standard F316 for the permeability measurement. This standardis described in ASTM publication F316 “Standard Test Methods for PoreSize Characteristics of Membrane Filters by Bubble Point and Mean FlowPore Test,” which is incorporated herein by reference. In some instancesthis test can be used as a quality control after configuring a mat basedon other measurements such as percent porosity.

Further, average pore diameter and average pore area of an ePTFE orserially deposited mat may be calculated programmatically using softwareto analyze an image, such as an SEM. For example, an SEM may beevaluated using software analysis to measure various characteristics ofa material layer. As part of this exemplary process, the SEM image mayfirst be converted to a “binary image,” or an image showing only blackand white portions, as discussed above. The binary image may then beanalyzed, the fibers or other features of the layer identified, andcharacteristics determined by comparing the relative numbers andplacements of each type of binary pixel. For example, an image may beconverted to a black and white image wherein black portions representgaps or holes in a serially deposited fiber mat while white portionsrepresent the fibers of the mat. The software thus identifies thepresence and position of fibers and pores or open portions of the fibermat.

Characteristics such as fiber width and pore size may be determined byanalyzing these binary images. Still further, characteristics ofrelative fibers, such as the number of fiber branches, intersections,bundles, fiber density, and so forth, may be determined through similaranalysis. In some instances, a code or script may be configured to makevarious analyses and calculations. U.S. patent application Ser. No.14/207,344, titled “Serially Deposited Fiber Materials and AssociatedDevices and Methods,” filed on Mar. 12, 2014, which is herebyincorporated by reference in its entirety, discusses various methods ofcharacterizing and evaluating construct layers.

In determining average pore size, an image may be evaluated todistinguish between areas comprising fibers and open areas, such as bycreating a binary image as discussed above. Pores, or areas within afiber mat encapsulated by intersecting or branched fibers, may then beidentified. To determine the average pore diameter, a large sample ofpores may be randomly selected from the target image. In some instances,between 50 and 300 pores may comprise the sample. The diameter of aparticular pore may be calculated by tracing multiple diameters of equalangular spacing around the pore through the centroid of the pore. Insome embodiments, 30 such diameters were used to determine a calculatedpore size. The measured diameters are then averaged to determine thecalculated effective diameter of the pore. The area of each identifiedpore may also be computed based on the pixel area of each pore. Eachpore identified for sampling may be manually checked to confirm properidentification of pores. The average pore diameter of a fiber mat maythen be computed by averaging the calculated effective diameters of theidentified pore. Again, material total porosity may also be determinedby the percentage of dark pixels to light pixels in the image.

FIGS. 3A-3C are schematic depictions of an exemplary medical appliance100. Specifically, FIG. 3A is a perspective cut-away view of the medicalappliance 100. FIG. 3B is a cross-sectional view of the medicalappliance 100 taken through line 3B-3B of FIG. 3A. FIG. 3C is anothercross-sectional view showing the layers of the medical appliance 100.

The medical appliance 100 of FIGS. 3A-3C may be configured as a vascularstent-graft. In the illustrated embodiment, the medical appliance 100 isshown with four distinct layers disposed about a scaffolding structure130. In the illustrated embodiment, the medical appliance comprises afirst layer 110 of rotationally spun PTFE. The rotationally spun PTFEfirst layer 110 defines the luminal surface of the medical appliance100. This luminal first layer 110 may be designed to interact with bloodflow within the vasculature. For example, the microporous structure ofthe rotationally spun first layer 110 may be configured to accommodateor allow endothelial cell growth on the luminal surface of the medicalappliance 100 when disposed within the vasculature of a patient.Alternatively or additionally, it is within the scope of this disclosureto use any serially deposited material on the luminal surface of themedical appliance 100. For example, rotational spun PTFE, electrospunPTFE, or other polymers may be used on this layer.

Serially deposited layers within the scope of this disclosure maycomprise a wide variety of characteristics. For example, seriallydeposited layers with a percent porosity between 35% and 75%, includingbetween 40% and 60%, and between 45% and 55%, are within the scope ofthis disclosure. Similarly, serially deposited layers with an averagefiber diameter between 0.25 micron and 2.5 micron, including between 0.5micron and 1.75 micron, and between 0.75 micron and 1.25 micron, arewithin the scope of this disclosure. Average pore diameter for seriallydeposited layers within the scope of this disclosure may range from onemicron to five micron, including from two micron to four micron and fromtwo micron to three micron. Finally, the average pore area of seriallydeposited layers within the scope of this disclosure may range fromthree square micron to 15 square micron, including from four squaremicron to 10 square micron, and from four square micron to eight squaremicron. Any serially deposited layer forming a portion of a constructdescribed herein may be configured with any of these properties.

In the illustrated embodiment, the medical appliance 100 comprises asecond layer 120 disposed radially around the first layer 110. Thesecond layer 120 may be configured to reinforce or otherwise strengthenthe first layer 110 of rotational spun material. In some embodiments,this second layer 120 may comprise ePTFE. The ePTFE layer may reinforcethe rotational spun first layer 110. For example, the ePTFE layer mayincrease the tensile strength, burst strength, hoop strength, or otherproperties of the medical appliance 100 as compared to a deviceutilizing only serially deposited fibers.

In some embodiments, the ePTFE may comprise densified ePTFE and/or ePTFEwith a small IND. The ePTFE second layer 120 may be configured with lowporosity and high work history to create a high-strength layer.

ePTFE layers within the scope of this disclosure may be configured witha variety of properties. For example, ePTFE layers with an averageinternodal distance (IND) of less than 80 micron, including less than 70micron, less than 60 micron, less than 50 micron, less than 40 micron,less than 30 micron, less than 20 micron, and less than 10 micron, arewithin the scope of this disclosure. Additionally, exemplary ePTFElayers within the scope of this disclosure may have an average IND ofless than 10, nine, eight, seven, six, five, four, three, two, or onemicron.

Additionally, ePTFE layers within the scope of this disclosure may havepercent porosities between 40% and 80%, including percent porositiesgreater than 50%. Further, such layers may have an average pore diametergreater than 1 micron, including between one micron and three micron.Average pore area may be greater than two square micron, includingbetween two square micron and 15 square micron. Finally, the averagefibril diameter of the ePTFE layer may be greater than 0.2 micron,including between 0.2 micron and 0.6 micron.

One exemplary ePTFE layer may have an IND of 10 micron, a percentporosity of 75%, average pore diameter of 4.38 micron, average pore areaof 14.7 square micron, and average fibril thickness of 0.33 micron. Asecond exemplary ePTFE layer may have an IND of 10 micron, a percentporosity of 65%, average pore diameter of 3.5 micron, average pore areaof 10.6 square micron, and average fibril thickness of 0.35 micron. Athird exemplary ePTFE layer may have an IND of 10 micron, a percentporosity of 50%, average pore diameter of 2.78 micron, average pore areaof 7.5 square micron, and average fibril thickness of 0.5 micron.

ePTFE layers according to the three exemplary layers above, as well asePTFE layers within any of the ranges disclosed herein, may be used inmultilayered constructs within the scope of this disclosure.

As compared to serially deposited layers, ePTFE layers may have agreater tensile strength, creep resistance, or other mechanicalproperties. For example, a multilayered construct may be comprised ofboth serially deposited layers and ePTFE layers wherein at least oneePTFE layer has five to 10 times greater tensile strength than at leastone serially deposited layer within the same construct.

Multilayered coverings or constructs wherein one or more layers of ePTFEprovide at least 90% of at least one mechanical property (such astensile strength, hoop strength, burst strength, and/or creepresistance) of the covering or construct are within the scope of thisdisclosure. In some instances such a construct may have no scaffoldingstructure. In other embodiments, the comparison of properties may onlyrefer to the properties provided by the covering portion, meaning thelayers of material disposed about a scaffolding structure, but notincluding the scaffolding structure. Still further, this comparison ofproperties may refer to the properties of the entire construct,including a scaffolding structure. Furthermore, coverings or constructswherein at least 85%, 80%, 75%, 70%, and 65% of at least one mechanicalproperty is provided by one or more layers of ePTFE are within the scopeof this disclosure.

In the illustrated embodiment, the scaffolding structure 130 is disposedaround the second layer 120 of the medical appliance 100. Thisscaffolding structure 130 may comprise a metal stent—for example, astent composed of nitinol, stainless steel, or alloys thereof.Additionally, other materials, such as polymer scaffolds, are within thescope of this disclosure. In some embodiments, the scaffolding structure130 may be understood as a third layer of the medical appliance 100. Forexample, as the scaffolding structure 130 may be disposed between othersuch layers (such as the second layer 120 and the fourth layer 140) iscan be understood as representing a layer of the medical device 100.Still further, in some embodiments the scaffolding structure maycomprise a relative tight lattice, including a polymer lattice, whichmay tend to form a layer of a medical appliance 100. References hereinto a multilayered construct or multilayered component may be understoodas referring to the entire medical appliance 100, including thescaffolding structure, or may apply only to layers of material (such as110, 120, 140, and 150) disposed about a scaffolding structure 130considered separately from the scaffolding structure 130.

The medical appliance 100 may further comprise an impermeable layer. Forexample, in the illustrated embodiment, the fourth layer 140 maycomprise a polymer layer that is impermeable to cellular growth, fluidpassage, or both. An impermeable layer may be configured to preventfluid leakage across the medical appliance and/or prevent cellulargrowth across the appliance. Containment of cellular growth across theappliance may lengthen the useful life of the appliance, as bodilytissues are prevented from growing through the medical appliance andoccluding the lumen thereof.

In some embodiments, the impermeable fourth layer 140 may comprisefluorinated ethylene propylene (FEP) that may be sprayed, dipped, orlaminated onto the construct. FEP layers within the scope of thisdisclosure may thus be applied as a film or membrane which is rolledonto or otherwise applied to a construct, as well as applied as a liquidor solution applied by spraying or dipping.

The medical appliance 100 may further comprise a fifth layer 150disposed around the impermeable fourth layer 140. This fifth layer 150may define an abluminal surface of the medical appliance 100. In someinstances, this fifth layer 150 may comprise ePTFE and may be densifiedand/or have a relatively small IND or pore size. This layer may beconfigured to provide strength to the construct and may or may notcomprise ePTFE having the same properties as the second layer 120 of theillustrated construct.

In some embodiments, the fourth layer 140 and the fifth layer 150 may beconstructed as a composite layer. For instance, a fifth layer 150comprising ePTFE may be sprayed or dipped with FEP such that the FEPcoats the ePTFE and fills in the pores and openings in the ePTFE. Acomposite layer of ePTFE and FEP may thus be configured with theproperties and functions of both the fourth layer 140 and fifth layer150.

Any of the layers discussed above (110, 120, 140, 150) may be comprisedof one or more sublayers. For example, if the first layer 110 iscomprised of serially deposited fibers, the first layer 110 may, inturn, comprise multiple sublayers of serially deposited fibers or fibermats. In an exemplary embodiment, the first layer 110 may thus consistof a first sublayer comprising serially deposited fibers and a secondsublayer also comprising serially deposited fibers. The sublayers may bedeposited at different times during manufacture and/or may be sinteredseparately, for example. The first layer 110 may also include othermaterials, disposed between the sublayers, for example to aid incoupling the sublayers to each other. Any number of sublayers may becombined within a single layer.

In some embodiments, the wall thickness of a multilayered covering for amedical device may be between 50 micron and 500 micron, includingbetween 50 micron and 450 micron, between 50 micron and 400 micron,between 50 micron and 350 micron, between 50 micron and 300 micron,between 50 micron and 250 micron, between 50 micron and 200 micron,between 50 micron and 150 micron, and between 75 micron and 125 micron.

The wall thickness of any individual layer within a multilayeredconstruct may be between five micron and 100 micron, including betweenfive micron and 75 micron, between five micron and 60 micron, between 25micron and 75 micron, between 10 micron and 30 micron, and between fivemicron and 15 micron. Any layer described herein may fall within any ofthese ranges, and the thicknesses of each layer of a multilayeredconstruct may be configured such that the total wall thickness of thecovering falls within the ranges described above.

Multilayered constructs that have more or fewer layers than theexemplary medical appliance 100 are likewise within the scope of thisdisclosure. For example, constructs having two, three, four, five, six,seven, or more layers are all within the scope of this disclosure. Insome embodiments, a single layer may be used to provide thecharacteristics associated with two or more layers in the exemplarymedical appliance 100. For example, ePTFE with a sufficiently small INDmay be substantially impermeable to tissue ingrowth and/or fluidpassage. Therefore, in some embodiments, a single layer of low-porosityePTFE may provide the characteristics associated with the second 120,fourth 140, and fifth 150 layers of the exemplary medical appliance 100.A medical appliance comprising a single luminal layer of seriallydeposited fibers and a single layer of ePTFE is within the scope of thisdisclosure.

Further, the order of the layers may be varied. For example, any of thelayers described in connection with the exemplary medical appliance 100may be disposed in any relative order, with the exception that a layerconfigured as a blood-contacting layer of the device (if present) willbe disposed on the luminal surface of the construct.

Furthermore, medical appliances within the scope of this disclosure maybe manufactured in a variety of ways. Each layer may be individuallyformed then disposed on the construct, or one or more layers may beformed on the construct in the first instance.

With reference to the medical appliance 100 of FIGS. 3A-3C, a method ofmanufacture may comprise serially depositing PTFE fibers on a mandrel orother collection surface and sintering the fibers. This layer ofserially deposited fibers may form the first layer 110 of the medicalappliance 100.

A second layer 120 may then be applied to the medical appliance 100.This second layer 120 may comprise ePTFE and may be densified. In someembodiments, the ePTFE may be obtained as a sheet which is appliedaround the first layer 110.

Additionally, in some embodiments the second layer 120 may be appliedaround the first layer 110 before the first layer 110 is sintered.Sintering of the first layer 110 while the second layer 120 is disposedtherearound may facilitate bonding between the first 110 and second 120layers. Similarly, in some embodiments, the second layer 120 may beapplied as unsintered ePTFE around the first layer 110, which in turnmay comprise unsintered serially deposited PTFE fibers. Accordingly, thefirst 110 and second 120 layers may be simultaneously sintered, whichmay facilitate bonding between the layers. Any layer of PTFE, includingserially deposited layers and layers of ePTFE, may be applied as anunsintered layer.

In some embodiments, the mechanical properties of an ePTFE layer may bederived from the relative disposition of ePTFE sublayers which comprisethe overall ePTFE layer. Each sublayer may impart different propertiesto the overall construct. For example, the sublayers may be stronger inthe direction the ePTFE was expanded than in a transverse direction.Application of such sublayers such that the axis of expansion of eachsublayer is perpendicular to the axis of expansion of adjacent layersmay create a layer of ePTFE with more uniform longitudinal and radialproperties. Constructs within the scope of this disclosure may compriseePTFE sublayers disposed such that the axis of expansion of a firstlayer is disposed at any angle to the axis of expansion of an adjacentlayer. Further, constructs wherein the axis of expansion of an ePTFEsublayer is aligned with the central axis of a prosthesis, for examplethe longitudinal axis of a tubular prosthesis, are within the scope ofthis disclosure.

In some embodiments this may be done by obtaining a strip of ePTFE thatis narrower than the length of the medical appliance 100. The strip maybe helically wrapped around the first layer 110 of the medical appliance100. In some instances the strip may be wrapped at about 45° to thelongitudinal axis of the medical appliance 100. The strip may comprise asublayer of the second layer 120. A second sublayer may be applied, alsoat about 45° to the longitudinal axis of the medical appliance 100, butapplied such that the axis of expansion of the second sublayer isperpendicular to the first strip applied. The combined strength of thesublayers may thus be arranged such that the sum of the strength of thesublayers is similar in the longitudinal and radial directions of themedical appliance 100. Any other angle of relative positioning ofsublayers is within the scope of this disclosure, and the relativeangles may be configured to create a construct with certain propertiesand strengths in various directions.

A metal or polymer scaffolding structure 130 may then be applied aroundthe second layer 120 of the medical appliance 100. The fourth layer 140may then be applied. The fourth layer 140 may comprise FEP and may beapplied as a film, dipped, sprayed, or otherwise applied. Finally, thefifth layer 150 may be applied around the fourth layer 140. The fifthlayer 150 may or may not be applied in the same manner as the secondlayer 120 and may or may not have substantially the same properties asthe second layer 120.

In embodiments wherein the fifth layer 150 comprises PTFE, includingePTFE, the fifth layer 150 may or may not be sintered at the same timeas other layers, for example, the second layer 120. In some embodiments,the first 110 and second 120 layers may first be applied and sintered(either separately or simultaneously), the scaffolding structure 130 maythen be applied, followed by the fourth layer 140. In some embodiments,the fourth layer 140 may comprise FEP and may be applied as a film or asa liquid or solution. In embodiments wherein the fourth layer 140 is FEPand the fifth layer PTFE, such as ePTFE, the fifth layer 150 may besintered after it is applied around the fourth layer 140. In some suchembodiments, a film FEP fourth layer 140 may bond to adjacent layersduring the heating of the construct to sinter the fifth layer 150. Againthe first 110 and second 120 layers may be previously sintered.

Methods of deploying a medical appliance, such as medical appliance 100,within the body are also within the scope of this disclosure. Similarly,methods of promoting endothelial growth while resisting transmuraltissue growth across the medical appliance are within the scope of thisdisclosure. For example, deployment of a medical appliance having ablood-contacting layer configured to promote endothelial growth and atleast one other layer configured to resist tissue growth through thelayer would be related to such a method.

FIG. 4 is a cross-sectional schematic view of the medical appliance 100deployed within a body lumen 50. As shown, when the medical appliance100 is so deployed, the fifth layer (150 of FIG. 3A), which may comprisean abluminal surface of the medical appliance 100, may be disposed indirect contact with the wall of the body lumen 50. The first layer (110of FIG. 3A), which may comprise a luminal surface of the medicalappliance 100, may be disposed in direct communication with fluidflowing through the body lumen 50. Characteristics of the various otherlayers of the medical appliance 100 may also affect the interactionbetween the body lumen 50 and the medical appliance 100, though theselayers may not be in direct contact with a surface of the body lumen 50.For example, a cellular or fluid impermeable layer may prevent tissue orfluid from crossing the wall of the medical appliance 100, though such alayer may or may not be disposed in direct contact with the body lumen50.

FIG. 5 is a perspective view of a scaffolding structure 200 for astent-graft. Such scaffolding structures may be coupled to coverings,including layered coverings, and may be configured to provide supportand structure to the stent-graft. For example, a scaffolding structure,such as scaffolding structure 200, may be configured to resist radialcompression of a stent-graft. Though references below may be directed tothe scaffolding structure 200, it will be understood, by one havingskill in the art and having the benefit of this disclosure, thatdisclosure relevant to the scaffolding structure 200 may analogouslyapply to a stent-graft or covered stent composed of the scaffoldingstructure 200.

In some embodiments, the scaffolding structure 200 may be configuredwith different resistance to radial force along the longitudinal lengthof the scaffolding structure 200. For example, in the illustratedembodiment, the scaffolding structure 200 comprises a proximal portion202, a mid-body portion 204, and a distal portion 206. The scaffoldingstructure 200 may be configured such that it provides greater resistanceto radial compression in one or more of these portions 202, 204, 206 ascompared to at least one other portion 202, 204, 206 of the scaffoldingstructure 200. Differing resistance to radial force along the length ofthe scaffolding structure 200 may be designed to provide strength incertain areas (such as an area to be treated, such as an aneurysm) whileproviding softer portions of the scaffolding which may allow thescaffolding structure 200 to interact with healthy portions of the bodyin a more atraumatic way. Thus one or more portions of a scaffoldingstructure may be configured to hold open diseased tissue within the bodylumen 50.

The radial resistance of the scaffolding structure 200, and anystent-graft comprising the scaffolding structure 200, may be a result ofthe material used to create the scaffolding structure 200; variations inthe structure of the scaffolding structure 200, such as the degree towhich the scaffolding structure 200 comprises a more open or more closeddesign; and other design parameters. In some embodiments within thescope of this disclosure, the radial force along portions of the samescaffolding structure, stent, or stent-graft may vary by between 10% and30%, between 30% and 60%, between 60% and 100%, more than 100%, and morethan 200%.

In some embodiments, the scaffolding structure 200 may be configuredsuch that the resistance to radial compression of the scaffoldingstructure 200 is greater in the mid-body portion 204 of the scaffoldingstructure 200 as compared to the proximal 202 and/or distal 206 portionsthereof. In other embodiments the mid-body portion 204 may have lessresistance to radial compression or, in other words, may be softer thanthe proximal 202 and/or distal 206 portions thereof. Still further, insome embodiments the proximal 202 and/or distal 206 portions of ascaffolding structure 200 may be configured to reduce tissue aggravationat the edge of the scaffolding structure 200. In some instances theresistance to radial compression of one or more ends of the scaffoldingstructure 200 may be configured to reduce the occurrence of edgestenosis. Moreover, the resistance to radial compression of one or moreends of the scaffolding structure 200 may be configured to promoteendothelial cell growth on a surface of a stent-graft coupled to thescaffolding structure 200. The resistance to radial compression alongone or more portions of the scaffolding structure 200 may be configuredto match the compliance of a body vessel in which the scaffoldingstructure 200 is designed for deployment.

Scaffolding structures 200 may comprise metals, including stainlesssteel, nitinol, various super elastic or shape memory alloys, and soforth. Scaffolding structures 200 may also comprise polymers. Further,scaffolding structures 200 may comprise one or more biologic agents,including embodiments wherein a metal or polymeric scaffolding structureis integrated with a drug or other biologic agent.

Scaffolding structures 200 may be formed in a variety of ways. In someembodiments, the scaffolding structure 200 may be formed of a wire.Further, the scaffolding structure 200 may be formed from a tube ofmaterial, including embodiments wherein the scaffolding structure 200 iscut from a tube of material. Scaffolding structures 200 may be formedusing laser cutting, etching processes, and powdered metallurgy andsintering processes; formed from molds; and formed using rapidmanufacturing techniques.

A stent or stent-graft, with or without a scaffolding structure such asscaffolding structure 200, may be configured to exert an outward radialforce when disposed within a body lumen. This force may be configured tokeep the lumen open, prevent restenosis, inhibit migration of the stentor stent-graft, and so forth. However, stents or stent-grafts whichsubject body lumens to high radial forces may provoke an unwantedbiologic response and/or result in unnecessary trauma to the body lumen.Accordingly, a stent or stent-graft may be configured to exert radialforce within a range that is acceptable for healing and trauma, whilestill achieving treatment goals.

Some stents or stent-grafts may be configured such that the stent orstent-graft resists localized compression, for example due to a point orpinch force, even when the localized force exceeds the circumferentialoutward radial force of the stent or stent-graft. In other words, thestent may be configured to resist relatively high point forces (forexample, as may be exerted by a ligament or other biologic structure) onthe stent or stent-graft without exerting high radial forces on theentire body lumen.

Stents or stent-grafts within the scope of this disclosure may beconfigured such that the point force required to fully collapse thestent is between five N and 15 N, including between 7.5 N and 12.5 N.Stents or stent-grafts within the point force ranges disclosed above mayhave a lower circumferential radial outward force. For example, stentsor stent-grafts within the scope of this disclosure may have a radialoutward force at 20% oversizing of between 0.3 N/mm and 1.3 N/mm,including between 0.4 N/mm and 1 N/mm. Thus, the point force required tofully collapse the stent may be significantly greater than the radialoutward force exerted by the stent on a body lumen.

Multilayered stent covers within the scope of this disclosure may betested by pressurizing water within the lumen of a stent according tothe present disclosure. By increasing the water pressure, the burststrength and water permeability of the stent can be determined. Waterentry pressure is herein defined as the internal water pressure at whicha second bead of water forms on the outside of the tubular structurebeing tested. The device does not burst or fail in the water entrypressure test. Medical devices within the scope of this disclosure mayhave water entry pressures between zero psi and 10 psi, includingbetween four psi and eight psi. Furthermore, medical devices within thescope of this disclosure may have water entry pressures greater thanfive psi, greater than 10 psi, greater than 20 psi, greater than 30 psi,greater than 40 psi, or greater than 50 psi.

The examples and embodiments disclosed herein are to be construed asmerely illustrative and exemplary, and not as a limitation of the scopeof the present disclosure in any way. It will be apparent to thosehaving skill in the art with the aid of the present disclosure thatchanges may be made to the details of the above-described embodimentswithout departing from the underlying principles of the disclosureherein. It is intended that the scope of the invention be defined by theclaims appended hereto and their equivalents.

The invention claimed is:
 1. A multilayered vascular prosthesis,comprising: a luminal surface comprising a serially deposited fiberlayer; and an expanded polytetrafluoroethylene (ePTFE) layer coupled tothe serially deposited fiber layer, wherein, the ePTFE layer comprisesone or more sublayers of ePTFE, and an axis of longitudinal expansion ofat least one of the ePTFE sublayers is disposed at an angle to an axisof longitudinal expansion of at least one adjacent ePTFE sublayer;wherein at least one of the ePTFE sublayers is configured to beimpermeable to red blood cell migration; and wherein the one or moresublayers of ePTFE comprise different average pore sizes.
 2. Themultilayered vascular prosthesis of claim 1, wherein the axis oflongitudinal expansion of at least one of the ePTFE sublayers isdisposed at an angle between 0 degrees and 90 degrees to the axis oflongitudinal expansion of at least one adjacent ePTFE sublayer.
 3. Themultilayered vascular prosthesis of claim 1, wherein the axis oflongitudinal expansion of at least one of the ePTFE sublayers isperpendicular to the axis of longitudinal expansion of at least oneadjacent ePTFE sublayer.
 4. The multilayered vascular prosthesis ofclaim 1, wherein the axis of longitudinal expansion of at least one ofthe ePTFE sublayers is at an angle to a longitudinal axis of themultilayered vascular prosthesis.
 5. The multilayered vascularprosthesis of claim 1, wherein an average pore size of at least one ofthe ePTFE sublayers is different than an average pore size of at leastone adjacent ePTFE sublayer.
 6. The multilayered vascular prosthesis ofclaim 1, wherein pores of at least one of the ePTFE sublayers aremisaligned with pores of at least one adjacent ePTFE sublayer such thata tortuous path is defined between the pores of the sublayers.
 7. Themultilayered vascular prosthesis of claim 1, wherein at least one of theePTFE sublayers is coupled to a non-porous layer.
 8. A multilayeredvascular prosthesis, comprising: a luminal surface comprising a seriallydeposited fiber layer; and an expanded polytetrafluoroethylene (ePTFE)layer coupled to the serially deposited fiber layer, the ePTFE layerproviding at least 65% of the tensile strength, measured in at least onedirection, of a construct consisting of the serially deposited fiberlayer and the ePTFE layer; wherein the ePTFE layer comprises two or moresublayers of ePTFE, wherein the ePTFE layer is configured to beimpermeable to red blood cell migration across the ePTFE layer, andwherein pores of at least one of the ePTFE sublayers are misaligned withpores of at least one adjacent ePTFE sublayer.
 9. The multilayeredvascular prosthesis of claim 8, wherein an average pore size of at leastone of the ePTFE sublayers is different than an average pore size of atleast one adjacent ePTFE sublayer.
 10. The multilayered vascularprosthesis of claim 8, wherein at least one of the ePTFE sublayers iscoupled to a non-porous layer.
 11. The multilayered vascular prosthesisof claim 8, wherein an axis of longitudinal expansion of at least one ofthe ePTFE sublayers is disposed at an angle to an axis of longitudinalexpansion of at least one adjacent ePTFE sublayer.
 12. The multilayeredvascular prosthesis of claim 11, wherein the axis of longitudinalexpansion of at least one of the ePTFE sublayers is disposed at an anglebetween 0 degrees and 90 degrees to the axis of longitudinal expansionof at least one adjacent ePTFE sublayer.
 13. The multilayered vascularprosthesis of claim 11, wherein the axis of longitudinal expansion of atleast one of the ePTFE sublayers is disposed at an angle to alongitudinal axis of the multilayered vascular prosthesis.